Santos-Patarroyo, Sebastián

Introduction: Assessing baseline cardiovascular (CV) risk factors is crucial for identifying cancer patients at higher risk of cardiotoxicity (CT). While both CT specific scores, including Heart Failure Association-International Cardio Oncology Society (HFA-ICOS) and our institutional score, as well as general CV scores like Atherosclerotic cardiovascular disease (ASCVD), have been used to assess CT risk; in lymphoma patients undergoing anthracycline therapy, their utility remains unknown. Aim: Evaluate the performance of each risk score to predict CT in a cohort of newly diagnosed lymphoma patients undergoing anthracycline treatment, followed for a median of 5.4 years. Methods: 326 Hodgkin and non-Hodgkin lymphoma patients treated and followed from 2013 to 2021 were prospectively assessed. Baseline measurements of the three risk scores were obtained. ASCVD score was not assessed in patients >80 or <40 years old or without baseline cholesterol. CT was defined during or after one year of chemotherapy as severe, moderate, or mild according to 2022 ESC guidelines. Logistic regression and AUC were used to assess the association of each score and compare the models. Results: Among 326 patients, 78 developed CT (8 severe, 21 moderate, 49 mild). A high-risk score from HFA-ICOS was significantly associated with severe and moderate CT(OR: 6.1, p=0.001), sensitivity 37%, and specificity 88%. A very high-risk classification of the institutional score was associated with severe and moderate CT (OR: 8.4, p=0.006), sensitivity 44%, and specificity 81%. No association was found between the ASCVD score stratification and CT. When mild CT was included in the analysis, the AUC values were lower (see Table 1). Conclusions: Cardio-oncology risk scores were associated with severe and moderate CT, outperforming ASCVD, but their predictive capacity was weak. Incorporating other serum or imaging biomarkers into the models may improve the predictive accuracy of CT risk assessment.

Background: CD19 CAR T-cell therapy is a novel cancer treatment for B-cell malignancies. Systemic inflammation due to Cytokine Release Syndrome (CRS) can occur. Elevated levels of cytokines have been linked to valve damage. Hypothesis: Evaluate changes in valve morphology or progression of valvular heart disease in adult patients after CD19 CAR T-cell therapy and by clinical CRS grade. Methods: Patients that underwent CD19 CAR T-cell therapy with both a baseline and a post-treatment transthoracic echocardiogram (TTE) were included. Patient characteristics and outcomes were abstracted from the electronic medical record. CRS was categorized as CRS<2 and CRS ≥2 for all patients using the ASTCT 2019 criteria. Valve thickening was graded as a dichotomous variable. Valve disease (regurgitation or stenosis) was ranked on a 1-to-6-point numeric scale (none, mild, mild-moderate, moderate, moderate-severe, severe) and grade point value difference was calculated. Variables were compared by Chi Squared and Student’s t tests. Results: 114 patients were included with a median TTE follow-up of 44 days, 54% developed CRS ≥2 (Table 1a). Overall, no statistically significant changes in valve morphology and valve disease progression were observed in the cohort (Figure 1a, 1b). Among CRS groups, valve morphology changes and valve disease progression were similarly distributed (21% in CRS <2 vs 19% in CRS ≥2, p=0.623 and 28% in CRS <2 vs 24% in CRS ≥2, p=0.62 respectively) (Fig. 1a). In the cases that progression was observed, it was mostly mild, and regurgitation was the most common pattern (Fig. 1c). Conclusions: This is the first study to evaluate the incidence of cardiac valve disease progression or thickening in patients treated with CD19 CAR T therapies. We can conclude that no progression of valve disease or changes in valve morphology were observed in its entirety or by CRS groups. Longer follow up is needed to validate these findings.

Abstract Background The diagnosis of cardiotoxicity (CT) related to cancer therapy has gained significance due to its impact on morbidity and mortality. The 2022 cardio-oncology European Society of Cardiology (ESC) Guidelines defined CT as symptomatic if a patient has clinical heart failure or asymptomatic based on changes in the ejection fraction (EF) or global longitudinal strain (GLS). The role of right ventricular parameters, such as tricuspid annular plane systolic excursion (TAPSE) and right ventricular free wall strain (RVFWS), in predicting CT is unknown. AIM Evaluate if TAPSE and RVFWS can predict the development of CT in lymphoma patients treated with anthracyclines. Methods For this prospective observational study, Hodgkin & non-Hodgkin lymphoma patients (n=222) treated with anthracyclines were recruited from 2013 to 2021 and were followed for one year. Echocardiographic variables TAPSE and RVFWS were measured at baseline(T0), during treatment(T1), and up to 1 year after chemotherapy completion(T2). CT was defined according to the ESC guidelines excluding GLS changes. We performed: Kruskal-Wallis test to find differences at baseline values, logistic regression to evaluate the association of TAPSE and RVFWS with CT, area under the curve (AUC) of the receiving operator characteristic (ROC) to measure the discriminative test ability and two sample proportion test to calculate the negative predictive value (NPV). A p-value &lt;0.05 was considered significant. Results 222 patients were enrolled and 23 developed CT: 4.5% (n=10) at T1 and 6.2% (n=13) at T2. The median of RVFWS at T0 was significantly different in patients who developed CT compared to those who did not at T1 (CT-22% vs. no CT-27% p=0.04) and T2 (CT -23%, no CT -26.5% p=0.03). RVFW values at T0 were associated with CT at T1 (OR, 1.281 95% CI,1.09-1.52 p=0.002) and T2 (OR 1.23 95% CI,1.07-1.44 p=0.003). At T0 RVFWS cutoff value of -24% had an AUC of 0.85 for the prediction of CT at T1, with a sensitivity of 83% and specificity of 76% (p=0.03). At T0, RVFWS cutoff of -25% had an AUC of 0.80 for the prediction of CT at T2, with a sensitivity of 75% and specificity of 60%, (p=0.04). RVFWS absolute values &gt;26% at T0 and T1 had an NPV of 100% for the development of CT in T1 and T2. The median TAPSE at T0 was significantly different in patients who developed CT at T1 compared to those who did not (CT patients 18.7 mm vs no CT patients 23.6 mm p=0.04). TAPSE values at T0 were associated with CT development at T1 but not at T2 OR 0.76 (95% CI,0.66-0.87 p=&lt;0.001). At T0, TAPSE cutoff of 21.6 mm had an AUC of 0.77 for the prediction of CT at T1, with a sensitivity of 77% and specificity of 70% (p=0.03). Conclusions Baseline absolute RVFWS values &lt;24% and &lt;25% were associated with CT at T1 and T2, respectively. Values &gt;26% had an excellent NPV for the development of CT. Baseline TAPSE values &lt;21.6 were associated with CT at T1. These parameters should be evaluated in other cancer populations.TAPSE and RVFWS association with CTRVFWS and TAPSE at T0 to predict CT

Abstract Background Staging classification for severe aortic stenosis (AS) based on the extent of cardiac damage has been correlated with outcomes in the general population. This is categorized based on the following echocardiographic findings: stage 1 (increase in the left ventricular mass index; E/e’&gt;14; and left ventricular ejection fraction &lt;50%); stage 2 (left atrial volume index &gt;34ml/m2; moderate to severe mitral regurgitation and atrial fibrillation), stage 3 (systolic pulmonary hypertension&gt; 60mmHg and moderate to severe tricuspid regurgitation) and stage 4 (moderate to severe right ventricular dysfunction); its applicability in a cancer population exposed to chemo+/- radiotherapy and its correlation with MACE has not been explored. Purpose To evaluate if this staging system predicts MACE (cardiovascular death, myocardial infarction, coronary revascularization, stroke, and hospitalization for heart failure) at 18 months after TAVR in cancer patients who were previously exposed to cardiotoxic therapies. Methods We retrieved data of patients that underwent TAVR from 2013 to 2021. 544 patients were included in this study and divided in 3 groups: 187 patients with prior chest Radiotherapy and Chemotherapy (RT/CT), 155 with CT only, and 202 cancer patients not exposed to CT or RT control group. This was further subdivided in two groups based on the staging system in: stage ≤ 2 and ≥3. Fisher's exact test or chi-square was used to compare categorical variables and clinical outcomes among groups and ANOVA for continuous variables. Echocardiographic findings and correlation with the outcome were evaluated by a multivariable Cox model analysis and assessed by a proportional hazards model for time to event. Kaplan–Meier curves were performed to determine the event-free survival rate. Significance was considered as a p&lt;0.05. Results RT/CT had a higher prevalence of moderate to severe mitral regurgitation (11.8%) p &lt;0.001 and tricuspid regurgitation (13.9%) p=0.02. Stage ≥3 was (24.1%) in the RT/CT, (9.4%) in CT, and (16.1%) in controls p= 0.004. Additionally, stage ≥3 was a predictor of MACE at 18 months: RT/CT group HR 6.43 (3.06 – 13.1) p&lt;0.001, CT HR 4.49 CI (2.27 – 8.89) p&lt;0.001 and control HR 2.20 CI (1.13 – 4.26) p=0.02 (Table 1). MACE at 18 months for stage ≥3 was higher for all groups vs. stage ≤ 2. MACE at 18 months after TAVR was significantly higher in stage &gt;3 for RT/CT (57.4%) and CT only (61.2%) vs. CL (27.2%) p&lt;0.001 (Figure 1B). Conclusions In addition to predicting aortic stenosis risk in cancer patients before TAVR, cardiac damage staging is a strong predictor of MACE at 18 months in patients post-RT/CT and CT and suggests that these patients may benefit from earlier stratification for TAVR prior to reaching stage 3. Future studies with longer follow-up should be explored to evaluate its usefulness in this complex population.

Abstract Background Exercise stress echocardiography (ESE) is a non-invasive, radiation-free, and widely available technique that has demonstrated a reliable accuracy for the detection of coronary artery disease (CAD). Chest radiotherapy (RT) is associated with accelerated age-related atherosclerosis and fibrosis in a dose-dependent manner. ESE plays a role as a screening tool of RT induced heart disease, however, the prognostic value of changes in regional wall motion abnormalities in this population during ESE has not been evaluated. Methods This is a retrospective cohort study of breast cancer survivors treated with adjuvant RT that underwent ESE from 2000-2020 after treatment completion. Outcomes evaluated were: major adverse cardiovascular events (MACE: cardiovascular death, myocardial infarction, revascularization and stroke); and all-cause mortality. A univariate analysis was performed to characterize the population. Continuous variables were presented as means ± standard deviation (SD) or median with quartile 1 and 3 (Q1, Q3), and categorical variables as numbers and percentages. A Cox regression model adjusted by age and cardiovascular risk factors was used to evaluate variables associated with outcomes, and a time to first event approach was used. A p-value of &lt;0.05 was considered statistically significant. Results From 2000-2020, 507 patients, with a mean age 66 ± 10 years, underwent ESE at a median of 5.8 years after RT completion. The most prevalent comorbidities were dyslipidemia (59%), HTN (55%) and obesity (37%). 55% underwent RT for left-sided breast cancer and 45% for right-sided, and median RT dose was 6000 cGy. Baseline characteristics are presented in Table 1. Most patients underwent Bruce Protocol (92%). Patients exercised a mean time of 6.6 minutes achieving 7.3 METS and 109% of functional aerobic capacity (Table 2). At a median follow up of 7.8 years, 61 MACE events occurred. Predictors of MACE were double product, baseline and stress EF, baseline and peak regional wall motion abnormalities (RWMA), development of new ischemic RWMA, inability to reach 85% of maximum HR, and an abnormal EF response with stress after adjusting for age, HTN, DM, smoking history, dyslipidemia, obesity, prior MI and cancer staging (Fig 1). Predictors of all-cause mortality were METS, LV mass index, baseline and peak RWMA, development of new ischemic RWMA and an abnormal EF change with stress even after adjusting for variables described previously (Fig 2). Conclusions The development of new or worsening RWMA of just 2 segments with stress, was a significant predictor of MACE and all-cause mortality in a large cohort of breast cancer survivors undergoing multidisciplinary management including adjuvant RT. Special emphasis on management of cardiovascular comorbidities and closer surveillance are recommended for these patients.

(1) Background: Coagulase-negative staphylococci (CoNS) are an important group of organisms that can cause bloodstream infection (BSI) and infective endocarditis (IE). The prevalence of IE in patients with BSI due to different CoNS species, however, has received limited attention; (2) Methods: A retrospective study of adults with monomicrobial CoNS BSI who had undergone echocardiography and a risk factor analysis was done to determine the most common CoNS species that cause definite IE; (3) Results: 247 patients with CoNS BSI were included in the investigation; 49 (19.8%) had definite IE, 124 (50.2%) possible IE, and 74 (30.0%) BSI only. The latter two entities were grouped in one category for further analysis. The most common species in CoNS BSI was Staphylococcus epidermidis (79.4%) and most patients (83.2%) had possible IE/BSI only. 59.1% of patients with BSI due to S. lugdunensis had definite IE. The majority of CoNS were healthcare-associated/nosocomial bacteremia. Multivariable analysis demonstrated that valve disease (p = 0.002) and a foreign cardiovascular material (p < 0.001) were risk factors associated with definite IE. Patients with S. lugdunensis BSI had an 8-fold higher risk of definite IE than did those with S. epidermidis BSI and nearly a 13-fold higher risk than did patients with BSI due to other species of CoNS (p = 0.002); (4) Conclusions: The prevalence of definite IE in patients with BSI due to different CoNS species was significant. CoNS bacteremia, particularly with S. lugdunensis, confers a significant risk of IE, particularly in patients with a valve disease or intravascular foreign body material and should not be immediately dismissed as a contaminant.

Abstract Purpose/Objectives: Proton therapy is under investigation in breast cancer as a strategy to reduce heart and lung exposure, which is associated with late cardiopulmonary adverse events and secondary malignancy. To date, studies investigating postmastectomy radiotherapy (PMRT) with protons have used conventional fractionation. We hypothesized that condensing treatment to 15 fractions would be safe based on evidence that breast cancer is more sensitive to higher dose fractions than surrounding normal tissues. Materials/Methods: We conducted a randomized non-inferiority phase II trial comparing conventional and hypofractionated proton PMRT with primary endpoint of 24-month complication rate (defined as grade 3 or higher late adverse events using CTCAE, v 4.0 and/or unplanned surgical intervention in patients undergoing mastectomy with reconstruction). With a 10% non-inferiority margin the study ensured 80% power and had a one sided-type I error rate of 0.05. Cardiotoxicity was assessed with serial transthoracic conventional and 2-dimensional speckle tracking echocardiography (2D-STE). Eligibility included age ≥ 18 years with non-inflammatory breast cancer resected by mastectomy with indications for PMRT. Assignment of treatments was balanced with respect to immediate breast reconstruction (IBR). Conventional fractionation group received 50 Gy in 25 fractions of 2 Gy, and hypofractionation group received 40.05 Gy in 15 fractions of 2.67 Gy (RBE 1.1). Target volume included the chest wall and axillary, supraclavicular, and internal mammary lymph nodes. All patients were treated with multi-field optimized pencil beam scanning (intensity modulated proton therapy). Results: Between 2016 and 2018, 82 patients were enrolled and randomized (41 conventional, 41 hypofractionation). Median patient age was 52 years. 32.9% were staged T3-T4 and 79.3% node positive at diagnosis. 57 of 82 patients (69.5%) elected IBR. The median mean heart dose was 0.49 Gy and the median ipsilateral lung volume receiving 40% of prescription or greater (V40%) was 13.6%. No significant changes on conventional or 2D-STE at end-of-treatment or 3-month follow-up compared to baseline were observed. The rate of ≥ grade 2 acute dermatitis was lower with hypofractionation (44% vs 15%, p = 0.006). Other ≥ grade 2 acute adverse events including esophagitis (0 vs 5%), infection (5% vs 2.4%) and skin hyperpigmentation (7.3% vs 4.8%) were not significantly different between the two arms. With a median follow-up of 38.3 months, the 24-month complication rate was conventional 14.6% vs hypofractionation 17.1% (absolute difference 2.4%, p=0.17, 95% CI [-, 15.7%]). In patients with IBR, 6 of 28 (21.4%) conventional and 7 of 29 (24.1%) hypofractionated patients developed complications (p =0.80). There was no significant difference in 3-year disease-free survival between the conventional (89.4%; 95% CI 80.0 – 99.8%) and hypofractionated (92.4%, 95% CI 84.5 – 100.0%) arms (p = 0.91). One local recurrence occurred in the hypofractionated arm simultaneous with regional and distant relapse. The remaining 6 recurrences were isolated distant events. Conclusions: Proton PMRT provided excellent locoregional control and normal tissue sparing. There were no subclinical echocardiographic changes indicative of radiation-induced cardiac dysfunction. Hypofractionation resulted in comparable disease control, tolerability and reconstruction outcomes as conventional fractionation. Although non-inferiority of hypofractionation could not be established based on the upper bound of the 95% confidence interval for complication rate being greater than 10%, both conventional and hypofractionation may be considered appropriate regimens for ongoing phase 3 randomized trials comparing photon and proton radiotherapy. Citation Format: Robert Mutter, Sharmila Giri, Briant Fruth, Nicholas Remmes, Aman Anand, Kathryn Ruddy, Hector Villarraga, Sebastian Santos Patarroyo, Elizabeth Yan, Kenneth Merrell, Lisa McGee, Tamara Vern-Gross, Bradley Stish, Robert Gao, Judy C. Boughey, Sean Park, Kimberly Corbin, Carlos Vargas. Phase II randomized trial of conventional versus hypofractionated post-mastectomy proton radiotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS4-05.